Microspheres and related processes and pharmaceutical compositions

ABSTRACT

The instant invention provides microspheres and related processes and pharmaceutical compositions useful in the controlled delivery of a wide variety of active ingredients. In one embodiment, the microspheres comprise an active ingredient dispersed within a polymeric composition comprising a first pH insensitive hydrophobic polymer and second pH sensitive hydrophobic polymer, wherein the microspheres, in an aqueous environment having a pH of around 5 or greater, release the active ingredient in a substantially zero-order profile. In another embodiment, the microspheres comprise an active ingredient dispersed within a polymeric composition comprising a first pH insensitive hydrophobic polymer and second water-swellable polymer, wherein the microspheres, in an aqueous environment, release the active ingredient in a substantially zero-order profile. In both of these embodiments, the microspheres are prepared by a non-aqueous emulsion solvent evaporation method.

FIELD OF THE INVENTION

The instant invention provides microspheres and related processes andpharmaceutical compositions useful in the controlled delivery of a widevariety of active ingredients. In one enteric embodiment, themicrospheres comprise an active ingredient dispersed within a polymericcomposition comprising a first pH insensitive hydrophobic polymer andsecond pH sensitive hydrophobic polymer, wherein the microspheres, in anaqueous environment having a pH of around 5 or greater, release theactive ingredient in a substantially zero-order profile. In anotherembodiment, the microspheres comprise an active ingredient dispersedwithin a polymeric composition comprising a first pH insensitivehydrophobic polymer and second water-swellable polymer, wherein themicrospheres, in an aqueous environment, release the active ingredientin a substantially zero-order profile. In both of these embodiments, themicrospheres are prepared by a non-aqueous emulsion solvent evaporationmethod.

BACKGROUND OF THE INVENTION

Many drugs irritate the stomach, are destroyed by gastric juices, or arenot well absorbed in the stomach. Consequently, delivery of such drugsin the small intestine is preferred. Site-specific release of drugs inthe small intestine, however, poses unique controlled delivery problems.In order to deliver a drug in useful form and quantity by the oral routeto the small intestine, a dosage form must pass through the stomachwithout releasing a significant amount of drug. In adults, the smallintestine extends from duodenum to ileum and is 3.5-6 m long. The pH ofthe gastrointestinal tract (GI) tract gradually increases as one movesdown the GI tract from the stomach (pH 1.5-3) to the early parts of thesmall intestine, the duodenum (pH 6.5-7.6) to the distal part of thesmall intestine, the ileum (pH 6.9-7.9). The transit through the GItract is highly variable and depends on many factors like the fasted/fedstate of the subject, quality and quantity of food, size and density ofthe dosage form, concomitant administration of other drugs and physicalexercise. Gastric transit of single unit non-disintegrating dosage formshas been reported to vary from 15 minutes to more than 3 hours. L. C.Kaus, et al., On the intestinal transit of a single nondisintegratingobject, Int. J. Pharm., 14, 143-148, 1984. The small intestinalresidence time is fairly constant at 3-4 hours.

Irrespective of the preferred site of drug delivery, controlled releasedrug dosage forms are known to have many advantages over conventionaldosing. It is well known that patient compliance is better when the drugdosing is only once or twice daily. It has been reported that, as thenumber of doses per day increases, there is a greater risk that thepatient will either forget or neglect to take every dose. B. Malahy, Theeffect of instruction and labeling on the number of medication errorsmade by the patient at home, American Journal of Hospital Pharmacy, 32,867-859, 1966. Other major advantages are the optimization of drugconcentration in plasma and reduction of side effects, particularly fordrugs with low therapeutic indexes. For oral administration, advantagesof multiple-unit products include ready distribution over a large area,less variable release and release which is less dependent on gastrictransit time V. D. Vilivalam, et al., Development and evaluation ofcontrolled-release diclofenac microspheres and tableted microspheres, J.Micro-encapsulation, 11, 455-470, 1994 (“Vilivalam”). This potentiallyimproves drug absorption and reduces local irritation to the GI mucosa.Li S. P., et al., Recent advances in microencapsulation technology andequipment. Drug Dev. Ind. Pharm., 14, 353-376, 1988.

Microspheres are recognized as an effective method to achieve asustained release effect. Vilivalam. Matrix microspheres can be preparedfor many drugs and are very rugged. H. A. M. Sayed, J. C. Price, Tabletproperties and dissolution characteristics of compressed celluloseacetate butyrate microcapsules containing succinyl sulfathiazole. DrugDev. Ind. Pharm., 12, 577-587, 1986. A widely used method to preparematrix microspheres is emulsion-solvent evaporation. O'Donnell, et al.,Preparation of microspheres by the solvent evaporation technique,Advanced Drug Delivery Reviews, 28, 25-42, 1997; K. Suzuki, J. C. Price,Microencapsulation and dissolution properties of a neuroleptic in abiodegradable polymer, poly (dl-lactide), J. Pharm. Sci., 74, 1, 21-241985. The emulsion solvent evaporation method offers several advantages.For example, it is a simple process, pH adjustment is not required, theprocess can be carried out at low or moderate temperatures, and reactiveagents or catalysts are not needed. In this method, a dispersion of drugin polymer solution is emulsified in a liquid that is immiscible withthe polymer solution. The drug is encapsulated inside the polymerdroplet. A. Luzzi, J. Microencapsulation, J. Pharm. Sci., 59, 1367-1376,1970. Microsphere characteristics are greatly affected by processing andformulation variables. Variables such as stirring speed, drugsolubility, solvent type, temperature, morphology and drug loading maybe varied in the process. R. Jalil, et al., Biodegradable poly(lacticacid) and poly(lactide-co-glycolide) microcapsules: problems associatedwith preparative techniques and release properties, J.Microencapsulation, 7, 297-325, 1990, A. J. Shukla, J. C. Price, Effectof drug loading and molecular weight of cellulose acetate propionate onthe release characteristics of theophylline microspheres. Pharm. Res.,8, 1396-1400, 1991.

There is a continuing need for improved controlled-releasepharmaceutical compositions comprising microspheres that achievepredictable (ideally zero order) delivery of a wide variety of activeingredients in both acidic environments such as the stomach and inenvironments such as the small intestine where pH can exceed 6. Ideally,such compositions would facilitate the delivery of active ingredientswhich have a low therapeutic index (e.g., theophylline, in whichconcentration in the blood should be maintained in the range 10-20μg/ml). And preferably, such compositions would utilizecontrolled-release vehicles such as microspheres which are readilymanufactured and which are well-suited to meet to all of theaforementioned pharmacological objectives.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide controlled-releasepharmaceutical compositions that achieve predictable (ideally zeroorder) delivery of a wide variety of active ingredients in both acidicenvironments such as the stomach and in environments such as the smallintestine where pH can exceed 6.

It is a further object of the present invention to provide microspheresthat are useful in controlled-release pharmaceutical compositions andthat achieve predictable (ideally zero order) delivery of a wide varietyof active ingredients in both acidic environments such as the stomachand in environments such as the small intestine where pH can exceed 6.

It is a further object of the present invention to provide microspheresthat achieve predictable (ideally zero order) delivery of activeingredients with a low therapeutic index in both acidic environmentssuch as the stomach and in environments such as the small intestinewhere pH can exceed 6.

It is a further object of the present invention to provide microspheresthat are compatible with the physiocochemical properties of a widevariety of drugs, including drug dose size, drug solubility,gastrointestinal stability and pKa.

It is a still further object of the present invention to provide methodsof making microspheres that are useful in controlled-releasepharmaceutical compositions and that achieve predictable (ideally zeroorder) delivery of a wide variety of active ingredients in both acidicenvironments such as the stomach and in environments such as the smallintestine where pH can exceed 6.

SUMMARY OF THE INVENTION

In accordance with the above stated objects, the instant inventionprovides microspheres that are useful in controlled-releasepharmaceutical compositions and that achieve substantially zero orderdelivery of a wide variety of active ingredients in both acidicenvironments such as the stomach and in environments such as the smallintestine where pH can exceed 6. These microspheres prove particularlyuseful in delivering active ingredients such as theophylline which havea low therapeutic index. Significantly, in one embodiment, themicrospheres, upon dissolution in an aqueous environment having a pH of6 or greater, substantially deliver all of their active ingredient inabout 12 to 24 hours.

Microspheres of the instant invention may be formulated to deliver anextremely broad range of pharmaceutically active ingredients. Themicrospheres are especially useful for delivery of moderately non-polaractive ingredients. However, the microspheres can be formulated todeliver very soluble polar compounds and non-polar, non-solublecompounds by adjusting microsphere composition to slow dissolution (inthe case of polar active compounds) or increase solubility (in the caseof non-polar active compounds).

In one enteric embodiment of the instant invention particularly usefulfor delivering active ingredient in the small intestine, the inventionprovides microspheres comprising an active ingredient dispersed within apolymeric composition comprising a first pH insensitive hydrophobicpolymer and second pH sensitive hydrophobic polymer, wherein themicrospheres, in an aqueous environment having a pH of around 5 orgreater, release the active ingredient in a substantially zero-orderprofile, and wherein:

(a) the microspheres are formed by a non-aqueous emulsion solventevaporation method in which the first and second polymers and activeingredient are dispersed in an organic solvent to form a polymersolution phase, the polymer solution phase is emulsified into a secondcontinuous phase comprising a second solvent and a surfactant to form anemulsified dispersion system, and the emulsified dispersion system isagitated and organic solvent evaporated there from to form themicrospheres;

(b) the concentration of the second polymer as a percentage of totalpolymer in the polymer solution phase ranges from around 1% to 35% andtotal polymer concentration in the polymer solution phase ranges fromaround 5% to around 35%;

(c) microsphere particle diameter ranges from approximately 25 μm toapproximately 1,000 μm;

(d) the weight percentage of active ingredient in a microsphere rangesfrom around 5% to around 50%; and

(e) active ingredient concentration is highest in the microsphere core.

In another embodiment, the invention provides microspheres comprising anactive ingredient dispersed within a polymeric composition comprising afirst pH insensitive hydrophobic polymer and second water-swellablepolymer, wherein the microspheres, in an aqueous environment, releasethe active ingredient in a substantially zero-order profile, andwherein:

(a) the microspheres are formed by a non-aqueous emulsion solventevaporation method in which the first and second polymers and activeingredient are dispersed in an organic solvent to form a polymersolution phase, the polymer solution phase is emulsified into a secondcontinuous phase comprising a second liquid having limited solventability for the components of the polymer solution phase and asurfactant to form an emulsified dispersion system, and the emulsifieddispersion system is agitated and organic solvent evaporated there fromto form the microspheres;

(b) the concentration of the second polymer as a percentage of totalpolymer in the polymer solution phase ranges from around 0.25% to 10%,total polymer concentration in the polymer solution phase ranges fromaround 5% to around 35% (more preferably around 5% to 20%), and theviscosity of the polymer solution phase ranges from around 20 cps toaround 1000 cps, more preferably about 50 to about 300 cps;

(c) microsphere particle diameter ranges from approximately 25 μm toapproximately 1,000 μm;

(d) the weight percentage of active ingredient in a microsphere rangesfrom around 5% to around 50%; and

(e) active ingredient concentration is highest in the microsphere core.

Enteric microspheres of the instant invention are made by a non-aqueoussolvent evaporation method comprising:

(a) dispersing a first pH insensitive hydrophobic polymer, a secondpH-sensitive hydrophobic polymer, and an active ingredient in an organicsolvent to form a polymer solution phase;

(b) emulsifying the the polymer solution phase into a second continuousphase comprising a second liquid having limited solvent ability for thecomponents of the polymer phase and a surfactant to form an emulsifieddispersion system; and

(c) agitating the emulsified dispersion system and evaporating theorganic solvent therefrom to form the microspheres

wherein (1) the concentration of the second polymer as a percentage oftotal polymer in the polymer solution phase ranges from around 0.25% to10% and total polymer concentration in the polymer solution phase rangesfrom around 5% to around 35% (2) microsphere particle diameter rangesfrom approximately 25 μm to approximately 1,000 μm (3) the weightpercentage of active ingredient in a microsphere ranges from around 5%to around 50%, and (4) active ingredient concentration is highest in themicrosphere core. All polymers, solvents, and ingredient used in themicrospheres and related processes of the instant invention arebiocompatible.

Microspheres of the instant invention are also made by a non-aqueoussolvent evaporation method comprising:

(a) dispersing a first pH insensitive hydrophobic polymer, a secondwater-swellable polymer, and an active ingredient in an organic solventto form a polymer solution phase;

(b) emulsifying the the polymer solution phase into a second continuousphase comprising a second solvent and a surfactant to form an emulsifieddispersion system; and

(c) agitating the emulsified dispersion system and evaporating theorganic solvent there from to form the microspheres

wherein (1) the concentration of the second polymer as a percentage oftotal polymer in the polymer solution phase ranges from around 0.25% to10%, total polymer concentration in the polymer solution phase rangesfrom around 5% to around 35% (more preferably around 5% to around 20%),and the viscosity of the polymer solution phase ranges from around 20cps to around 1000 cps, more preferably around 50 cps to 300 cps,

(2) microsphere particle diameter ranges from approximately 25 μm toapproximately 1,000 μm (preferably, at least 75 μm within this range),(3) the weight percentage of active ingredient in a microsphere rangesfrom around 5% to around 50%, preferably around 20% to 40%; and (4)active ingredient concentration is highest in the microsphere core.

In preferred enteric embodiments of the instant invention, the first andsecond polymers are selected from the group consisting of celluloseacetate, cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate phthalate, cellulose propionate butyrate, andcombinations and mixtures thereof. In particularly preferredembodiments, the first polymer is cellulose acetate butyrate (CAB) andthe second polymer is cellulose acetate phthalate (CAP), the totalconcentration of CAB in the polymer solution phase is between around 7%to around 9%, and the total concentration of CAP in the polymer solutionphase as a percentage of total polymer is between around 1% to 3%.

In other preferred embodiments of the instant invention, the firstpolymer is selected from the group consisting of cellulose acetate,cellulose acetate propionate, cellulose acetate butyrate, cellulosepropionate butyrate, and combinations and mixtures thereof, and thesecond polymer is selected from the group consisting of alow-substituted cellulose ether or internally cross-linked cellulosederivatives of sodium carboxymethylcellulose,hydroxypropyl-methylcellulose (HPMC), a hydroxypropylcellulose (HPC), apoly(ethylene oxide), a hydroxy-ethylcellulose, or a hydrogel formingpolymer.

In particularly preferred embodiments, the first polymer is celluloseacetate butyrate (CAB) and the second polymer is hydroxypropylcellulose(HPC), the total concentration of CAB in the polymer solution phase isbetween around 7% to around 9%, and the total concentration of HPC inthe polymer solution phase as a percentage of total polymer is betweenaround 0.5% to 3%.

Most preferably, microspheres of the present invention are about 300microns (μm.) in size. Even more preferably, the microspheres arebetween 150 μm and 200 μm in size. However, the microspheres of thepresent invention may be formulated to achieve virtually any size lessthan 300 μm by adjusting agitation rates, adjusting viscosity of theemulsified dispersion phase, or increasing the temperature used duringformulation.

These and other features of the instant invention are described furtherin the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a log probability plot of particle size distributionsof CAB-CAP microspheres of the instant invention.

FIGS. 2-10 illustrate theophylline release profiles in HCl for differentsize CAB-CAP microspheres, or varying CAB:CAP ratio microspheres, of theinstant invention.

FIG. 11 illustrates Higuchi plots for different size fractions forCAB-CAP microspheres of the instant invention.

FIG. 12 illustrates theophylline release profiles in phosphate buffer(pH 7.5) for CAB-CAP microspheres of the instant invention.

FIG. 13 illustrates a log probability plot of particle sizedistributions of CAB-HPC microspheres of the instant invention.

FIGS. 14-19 illustrate theophylline release profiles in simulatedintestinal fluid for different size CAB-HPC microspheres, or varyingCAB:HPC ratio microspheres, of the instant invention.

FIGS. 20 and 21 illustrate theophylline release profiles for differentsize CAB-HPC microspheres of the instant invention compared to those ofCAB microspheres.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms have the following respectivemeanings.

“Biocompatible”: the polymers, solvents and other agents of theinvention must be biocompatible; that is they must not cause irritationor necrosis in the environment of use. The environment of use is a fluidenvironment and may comprise a subcutaneous or intramuscular portion orbody cavity of a human or animal.

“Enteric” as used herein means a composition comprising an activeingredient having an increased resistance to degradation in the uppergastrointestinal tract, and/or a decrease in the release or exposure ofactive ingredient in the upper gastrointestinal tract.

A “microsphere” as used herein means a “matrix microsphere” in whichactive ingredient particles are dispersed in direct contact with thepolymer matrix. Such a microsphere is a homogeneous or monolithicparticle in which the drug is dissolved or dispersed throughout thepolymer matrix. Release of drugs from a microsphere is a mass transportphenomenon involving diffusion of drug molecules from the region of highconcentration in the dosage form to a region of low concentration in thesurrounding environment. Mathematical release rate expressionsdescribing microspheres are provided in T. Higuchi, Mechanism ofsustained action medication, Theoretical analysis of rate of release ofsolid drug dispersed in solid matrices. J. Pharm. Sci., 52.

An “Emulsion-solvent evaporation process” or “non-aqueousemulsion-solvent evaporation process” can be used to make microspheresand involves dissolving or dispersing a drug in solution of one or morepolymers, e.g. a mixture of CAB and CAP, in single or mixed organicsolvent having low boiling point to form a polymer solution phase. Thephase is then emulsified into a continuous immiscible phase containing alow concentration of colloid or surfactant to stabilize the emulsionformed. Reduced pressure or heat is often applied to evaporate off theorganic solvent and the microspheres are collected by filtration orcentrifugation.

Emulsion-based processes used herein involve the preparation of twoseparate phases: a first phase (referred to herein as the “polymerphase” and also known as the “solvent” or “W” phase), which consists ofa dispersion or solution of an active agent in a solution of polymerdissolved in a first solvent, and a second phase (the “continuousdispersion medium (O-phase)”), which consists of a solution ofsurfactant and a second liquid (e.g., light or heavy mineral oil) thatis at least partially immiscible with the first solvent of the dispersedphase. After the first and second phases are prepared, they are combinedusing dynamic or static mixing to form an emulsion (also referred toherein as the “emulsified dispersion system”), in which microdroplets ofthe first phase are dispersed in the second phase. The microdropletsthen are hardened to form polymeric microspheres that contain the activeagent. The hardening step is carried out by removal of the first solventfrom the microdroplets, in the case of the instant invention byevaporation.

It is known that several variables may be varied, or must be considered,in employing an emulsion-solvent evaporation process. These includedrug/polymer ratio, the nature of the surfactant and organic phasevolume and their effect on the final product. Increasing thedrug/polymer ratio can decrease microsphere yield; a reduction in theamount of organic solvent (internal phase) can cause an increase inmicrosphere diameter along with a lowering of release rate.Immiscibility/miscibility characteristics of the solvent with the oilyphase plays an important role in microsphere formation; where ethylcellulose or similar polymers are used, microcapsule or microsphereformation mainly depends on solvent diffusion rate into the oily phaseand on drug solubility in the ethyl cellulose solvent. Variables such asstirring speed, drug solubility, solvent type, temperature, morphologyand drug loading have been reported frequently as being very importantin making microspheres by the process.

“Emulsify” means to form a stable dispersion of one liquid in a secondimmiscible liquid. An example of such would be milk. An “immiscible”liquid is a liquid which is not soluble in another substance or liquid,for example, oil in water. In contrast, two substances that are mutuallysoluble in all proportions are is said to be miscible.

“Surfactants” or “emulsifiers” that can be used in the instant inventioninclude but are not limited to anionic surfactants, nonionicsurfactants, polyoxyethylene-castor oil derivatives,polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose,lecithin, and sorbitan sesquioleate. Sorbitan sesquioleate (for example,Span 83 and Arlacel 83) and magnesium stearate are preferredsurfactants.

“Hydrophobic polymers” are polymers that are substantially insoluble inwater and that dissolve in organic solvents. As used herein, the termincludes pH insensitive polymers and pH-sensitive polymers.“Hydrophobic”, “pH insensitive” and “pH sensitive” as used herein arerelative terms and in making microspheres of the instant invention, thehydrophobicity and pH-sensitivity of each polymer when compared to theother(s) is determinative. “pH insensitive” implies that pH has alimited effect on polymer dissolution at a pH of around 5 or greater.“pH sensitive” implies that pH has a more pronounced effect on polymerdissolution at a pH of around 5 or 6 or greater than would be the casewith a “pH insensitive” polymer. “Hydrophobic polymers” includecross-linked polyvinyl alcohol, polyolefins or polyvinyl chlorides;regenerated, insoluble, non-erodible cellulose, acylated cellulose,esterified celluloses, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose acetatediethyl-aminoacetate; polyurethanes, polycarbonates, and microporouspolymers formed by co-precipitation of a polycation and a polyanionmodified insoluble collagen.

Exemplary esterified or acylated cellulose derivatives suitable for usein the instant invention as pH sensitive or pH insensitive hydrophobicpolymers include those which are substituted by one to three acetylgroups or by one or two acetyl groups and a further acyl radical otherthan acetyl, such as cellulose acetate dimethylamino acetate, celluloseacetate ethyl and methyl carbonate, cellulose acetate phthalate,cellulose acetate succinate, cellulose acetate chloroacetate, cellulosediacetate, cellulose triacetate, cellulose acetate ethyl oxalate,cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate,cellulose acetate methyl and butyl sulfonate, cellulose acetate octate,cellulose acetate laurate, cellulose acetate p-toluene sulfonate,cellulose acetate ethyl and methyl carbamate, cellulose acetatevalerate, cellulose acetate maleate, and the like, and combinations andmixtures thereof.

Preferred cellulose esters are cellulose acetate, cellulose acetatepropionate, cellulose acetate butyrate, cellulose acetate phthalate,cellulose propionate butyrate, and the like, and combinations andmixtures thereof. Such cellulose derivatives can be prepared by anyknown technique in the art (for example, see Kirk-Othmer, Encyclopediaof Chemical Technology, 3rd Edition, Vol. 5, John Wiley & Sons, NewYork, N.Y., 1979, p. 89-129; and Libscomb, A. G., Cellulose Acetate: ItsManufacture and Applications, Ernest Benn, Ltd. London, GB, 1933), orcan be obtained commercially (for example, from Eastman ChemicalProducts, Inc., Kingsport, Tenn.).

Particularly preferred cellulose esters that do not exhibit pH-dependentsolubility characteristics and act as pH insensitive hydrophobicpolymers in the instant invention include cellulose acetate butyrates(CAB). Particularly preferred cellulose acetate butyrates areCAB-171-15PG, CAB-381-0.1, CAB-381-20, CAB-500-5, and CAB-553-0.4, whichare all commercially available from Eastman Chemical Products, Inc.,Kingsport, Tenn.). In the foregoing description, the first two digitsindicate the approximate butyryl content at the triester stage, thethird digit indicates the number of hydroxyl groups for each fouranhydroglucose units, and the last digit(s) indicate the viscosity ofthe ester. CABs with higher butyryl content, such as greater than 30%,tend to be more effective in suppressing crystal formation. Particularlypreferred cellulose esters that do exhibit relative pH-dependentsolubility characteristics at pH's of around 5 or 6 or greater and canfunction as pH sensitive hydrophobic polymers include cellulose acetatephthalate (CAP). Those of ordinary skill in the art will be able toselect suitable combinations or mixtures of the aforementioned pHinsensitive and pH sensitive hydrophobic polymers for use in makingmicrospheres of the instant invention.

“Water-swellable polymers” includes a hydroxypropyl-methylcellulose(HPMC), a hydroxypropylcellulose (HPC), a poly(ethylene oxide), ahydroxyethylcellulose or a combination thereof. Water-swellable polymersalso include a low-substituted cellulose ether or internallycross-linked cellulose derivatives of sodium carboxymethylcellulose. Anespecially preferred type of HPMC for use in accordance with theinvention is an HPMC sold under the trademark Methocel (Dow ChemicalCo.) or equivalents. Suitable Methocels include the K grades such asMethocel K15M, Methocel K100M, Methocel K100LV and Methocel K4M. Othersuitable Methocels include the E, F and J grades. An especiallypreferred type of HPC for use in accordance with the invention is an HPCsold under the trademark Klucel (Hercules, Inc.) or equivalents.Suitable Klucels include Klucel LF, Klucel JF, Klucel GF, Klucel MF andKlucel HF. An especially preferred type of poly(ethylene oxide) for usein accordance with the invention is a poly(ethylene oxide) sold underthe trademark Sentry Polyox (Union Carbide Corp.) or equivalents.Suitable Polyoxs include the Polyox WSR grades such as Polyox WSRCoagulant, Polyox WSR-301, Polyox WSR-303, Polyox WSR N-12K, Polyox WSRN-60K, Polyox WSR-1105, Polyox WSR-205 and Polyox WSR N-3000.

Water-swellable polymers also include polymers that form hydrogels. Ahydrogel is defined as a substance formed when an organic polymer(natural or synthetic) is cross-linked via covalent, ionic, or hydrogenbonds to create a three-dimensional open-lattice structure which entrapswater molecules to form a gel. Naturally occurring and synthetichydrogel forming polymers, polymer mixtures and copolymers may beutilized as hydrogel precursors. Examples of materials which can be usedto form a hydrogel include polysaccharides such as alginate and modifiedalginates, synthetic polymers such as polyphosphazines, andpolyacrylates, which are crosslinked ionically, or block copolymers suchas Pluronics or Tetronics.™, polyethylene oxide-polypropylene glycolblock copolymers which are crosslinked by temperature or pH,respectively. Other materials include proteins such as fibrin, polymerssuch as polyvinylpyrrolidone.

“Organic solvent” as used herein includes halogenated hydrocarbons(e.g., dichloromethane, chloroform, carbon tetrachloride, etc.),alcohols (e.g., ethanol, methanol, etc.), acetonitrile, and acetone.These solvents can also be used as a mixture. The preferred organicsolvents are acetonitrile, and acetone. Acetone is particularlypreferred.

“Non-polar” as used herein means a composition that has lipophilicgroups or has sufficient lipophilic character such that the compositionis soluble in a hydrocarbon phase and “polar” as used herein means acomposition that has hydrophilic groups soluble in an aqueous phase.

The surfactant-containing “second solvent” used in the instant inventionmay be a substance belonging to any of the categories of polymers,mineral oils or vegetable oils, which are not miscible with the “organicsolvent” defined previously, and in which the hydrophobic orwater-swellable polymers are not appreciably soluble. Typical examplesare silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil,coconut oil, linseed oil, mineral oil, n-hexane, n-heptane, and mixturesthereof.

“Controlled release” generally refers to compositions, e.g.,pharmaceutically acceptable carriers, for controlling the release of anactive agent or drug incorporated therein, typically by slowing therelease of the active agent or drug in order to prevent immediaterelease. Such controlled release compositions and/or carriers are usedherein to prolong or sustain the release of an active agent or drugincorporated.

The phrase “substantially zero-order” as used herein means delivery ofan active agent at a release rate which is approximately constant oncesteady state is attained, typically within 12 hours or less afterdissolution in an aqueous environment. While variability in blood levelsof active agent are contemplated within the scope of this meaning oncesteady state release is attained, the depletion rate of active agentover the duration of use should typically not exceed about 10% per hourfor oral controlled release dosage forms but may be much slower forimplantable or transdermal dosage forms.

“Therapeutic index”: Toxicity and therapeutic efficacy of pharmaceuticalcompositions employing microspheres as described herein can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD 50 (the dose lethalto 50% of the population) and the ED 50 (the dose therapeuticallyeffective in 50% of the population). The dose ratio between toxic andtherapeutic effects is the “therapeutic index” and it can be expressedas the ratio between LD 50 and ED 50. Compounds which exhibit hightherapeutic indices are preferred. The data obtained from these cellculture assays and animal studies can be used in formulating a range ofdosage for use in humans. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the ED 50 withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition. (Seee.g., Fingl et al., 1975, in “The Pharmacological Basis ofTherapeutics,” Ch. 1 p. 1).

“Pharmaceutical compositions” comprising microspheres of the presentinvention may be formulated in a conventional manner using one or morepharmaceutically acceptable carriers. Pharmaceutically acceptablecarriers that may be used in these pharmaceutical compositions include,but are not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as prolamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polylactic acid, polyglycolic acid, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol,sucrose, lactose and wool fat.

Pharmaceutical compositions comprising microspheres of the presentinvention may be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intraperitoneally, or intravenously.

Sterile injectable forms of pharmaceutical compositions comprisingmicrospheres of the present invention may be aqueous or oleaginoussuspension. These suspensions may be formulated according to techniquesknown in the art using suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or diglycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as cetylalcohol or similar a similar alcohol.

Pharmaceutical compositions comprising microspheres of the presentinvention may be orally administered in any orally acceptable dosageform including, but not limited to, capsules, tablets, aqueoussuspensions or solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose, sucrose, microcrystallinecellulose and corn starch. Lubricating agents, such as magnesiumstearate and stearic acid, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions are required for oral use,the active ingredient is combined with emulsifying and suspendingagents. If desired, certain sweetening, flavoring or coloring agents mayalso be added.

Alternatively, pharmaceutical compositions comprising microspheres ofthe present invention may be administered in the form of suppositoriesfor rectal administration. These can be prepared by mixing the agentwith a suitable non-irritating excipient which is solid at roomtemperature but liquid at rectal temperature and therefore will melt inthe rectum to release the drug. Such materials include cocoa butter,certain mono-, di-, and triglycerides of long chain fatty acids andpolyethylene glycols.

Pharmaceutical compositions comprising microspheres of the presentinvention may also be administered topically, especially when the targetof treatment includes areas or organs readily accessible by topicalapplication, including diseases of the eye, the skin, or the lowerintestinal tract. Suitable topical formulations are readily prepared foreach of these areas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, pharmaceutical compositions comprisingmicrospheres of the present invention may be formulated in a suitableointment containing the active component suspended or dissolved in oneor more carriers. Carriers for topical administration of the compoundsof this invention include, but are not limited to, mineral oil, liquidpetrolatum, white petrolatum, propylene glycol, polyoxyethylene,polyoxypropylene compound, emulsifying wax and water. Alternatively, thepharmaceutical compositions can be formulated in a suitable lotion orcream containing the active components suspended or dissolved in one ormore pharmaceutically acceptable carriers. Suitable carriers include,but are not limited to, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, stearyl alcohol, 2-octyldodecanol, benzyl alcoholand water.

For ophthalmic use, pharmaceutical compositions comprising microspheresof the present invention may be formulated from very fine microspheresas suspensions in isotonic, pH adjusted sterile saline, or, preferably,as solutions in isotonic, pH adjusted sterile saline, either with ourwithout a preservative such as benzylalkonium chloride. Alternatively,for ophthalmic uses, the pharmaceutical compositions may be formulatedin an ointment such as petrolatum.

Pharmaceutical compositions comprising microspheres of the presentinvention may also be administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and may be prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,absorption promoters to enhance bioavailability, fluorocarbons, and/orother conventional solubilizing or dispersing agents.

The amount of active ingredient used in pharmaceutical compositionscomprising microspheres of the present invention will vary dependingupon the host treated, the particular mode of administration.

The term “active ingredient” (or “agent,” “drug,” “medicament” and“pharmaceutical”) is intended to have the broadest meaning and includesat least one of any therapeutic, prophylactic, pharmacological orphysiological active substance, cosmetic and personal care preparations,and mixtures thereof, which is delivered to a mammal to produce adesired, usually beneficial, effect. More specifically, any active agentthat is capable of producing a pharmacological response, localized orsystemic, irrespective of whether therapeutic, diagnostic, cosmetic orprophylactic in nature, is within the contemplation of the invention. Itshould be noted that the active agents can be used singularly or incombinations and mixtures.

There is no limitation on the type of active ingredient that can be usedin this invention. However, slightly non-polar active agents arepreferred. In particular, the microspheres of the instant invention areuseful in delivering active ingredients such as theophylline which havea low therapeutic index. (Theophylline concentration in the blood shouldbe maintained in the range 10-20 μg/ml.)

The active agents contained in the carrier composition can be indifferent forms depending on the solubility and release characteristicsdesired, for example as neutral molecules, components of molecularcomplexes, and pharmaceutically acceptable salts, free acids or bases,or quaternary salts of the same. Simple derivatives of the drugs such aspharmaceutically acceptable ethers, esters, amides and the like whichhave desirable retention and release characteristics but which areeasily metabolized at body pH, and enzymes, pro-active forms, pro-drugsand the like, can also be employed.

Steroidal hormones and active agents that generally tend to be poorlysoluble or insoluble can be used in the microspheres of the instantinvention and include, for example, Estrogenically effective steroidhormones such as Colpormon, Conjugated Estrogens, Estradiol (17.beta.-and .alpha.-) and its Esters (e.g., Acetate, Benzoate, Cypionate,Dipropionate Diacetate, Enanthate, Undecylate and Valerate), Estriol,Estrone, Ethinyl Estradiol, Equilenin, Equilin, Mestranol, Moxestrol,Mytatrienediol, Quinestradiol and Quinestrol; Progestagenicallyeffective steroid hormones such as Allylestrenol, Anagestone,Chlormadinone Acetate, Delmadinone Acetate, Demegestone, Desogestrel,3-Keto Desogestrel, Dimethisterone, Dydrogesterone, Ethinylestrenol,Ethisterone, Ethynodiol (and Diacetate), Flurogestone Acetate,Gestodene, Gestonorone Caproate, Haloprogesterone, (17-Hydroxy- and17-Acetate-) 16-Methylene-Progesterone, 17.alpha.-Hydroxyprogesterone(Acetate and Caproate), Levonorgestrel, Lynestrenol, Medrogestone,Medroxyprogesterone (and Acetate), Megestrol Acetate, Melengestrol,Norethindrone (Acetate and Enanthate), Norethisterone, Norethynodrel,Norgesterone, Norgestimate, Norgestrel, Norgestrienone,19-Norprogesterone, Norvinisterone, Pentagestrone, Progesterone,Promegestone, Quingestrone and Trengestone; Androgenically effectivesteroid hormones such as Aldosterone, Androsterone, Boldenone,Cloxotestosterone, Dehydroepiandrosterone, Fluoxymesterone, Mestanolone,Mesterolone, Methandrostenolone, Methyltestosterone,17.alpha.-Methyltesteosterone, 17.alpha.-Methyltestosterone3-Cyclopentyl Enol Ether, Norethandrolone, Normethandrone, Oxandrolone,Oxymesterone, Oxymetholone, Prasterone, Stanlolone, Stanozolol,Testosterone (Acetate, Enanthate, Isobutyrate, Propionate andUndecanoate), Testosterone 17-Chloral Hemiacetal, Testosterone17.beta.-Cypionate and Tiomesterone.

Other specific drugs which can be used in microspheres of the instantinvention include:

1. Alpha-Adrenergic Agonist agents such as Phenylpropanolamine andTalipexole.

2. Analgesics and/or Anti-Migraine such as Acetaminophen,Acetylsalicylic Acid, Buprenorphine, Codeine, Fentanyl, Hydomorphone,Lisuride, Salicylic Acid derivatives, Sufentanil and Sumatriptan.

3. Anti-Allergic agents such as Amlexanox, Astemizole, Azelastine,Cromolyn, Fenpiprane, Ibudilast, Nedocromil, Oxatomide, Pentigetide,Repirinast, Tranilast and Traxanox.

4. Anesthetic agents such as Benzocaine, Bupivicaine, Cocaine,Dibucaine, Dyclonine, Etidocaine, Lidocaine, Mepivacaine, Prilocaine,Procaine and Tetracaine.

5. Anoretic agents such as Fenfluramine, Mazindol and Phentermine.

6. Anti-Bacterial (antibiotic) agents including Aminoglycosides,B-Lactams, Cephamycins, Macrolides, Penicillins, Polypeptides andTetracyclines.

7. Anti-Cancer agents such as Aminolevulinic Acid, 5-Fluouracil,Methotrexate, Tamoxifen and Taxol.

8. Anti-Cholinergic agents such as Atropine, Eucatropine andProcyclidine.

9. Anti-Diabetic agents such as Glipizide, Glyburide, Glypinamide,Insulins, Repaglinide, Rosiglitazone and Troglitazone.

10. Anti-Emetic agents such as Acetylleucine Monoethanolamine,Alizapride, Benzquinamide, Bietanautine, Bromopride, Buclizine,Chlorpromazine, Clebopride, Cyclizine, Dimenhydrinate, Dipheniodol,Domperidone, Granisetron, Meclizine, Methalltal, Metoclopramide,Metopimazine, Nabilone, Ondansteron, Oxypendyl, Pipamazine,Piprinhydrinate, Prochlorperazine, Scopolamine, Tetrahydrocannabinols,Thiethylperazine, Thioproperzaine, Trimethobenzamide and Tropisetron.

11. Anti-Fungal agents such as Clortrimazole, Ketoconazole, Miconazole,Nystatin and Triacetin.

12. Antihistamine agents such as Tricyclics such as Ahistan,Etymemazine, Fenethazine, N-Hydroxyethylpromethazine Chloride,Isopromethazine, Mequitazine, Promethazine, Pyrathiazine, andThiazinamium Methyl Sulfate, and Loratadine and Clobenzepam.

13. Anti-Hyperlipoproteinemic agents such as Atorvastatin, Cerivastatin,Lovastatin, Pravastatin and Simvastatin.

14. Anti-Hyperthyroid agents such as Methimazole.

15. Anti-Inflammatory and/or Corticoid agents such as Beclomethasone,Betamethasone (and Acetate, Diproprionate and Valerate), Corticosterone,Cortisone, Deoxycortocosterone (and Acetate), Dexamethasone, Diclofenac,Fenoprofen, Flucinolone (and Acetonide), Fludrocortisone, Fluocinonide,Flunisolide, Fluradrenolide, Flurbiprofen, Halcinonide, Hydrocortisone(and Acetate), Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Ketorolac,Naproxen, Oxametacine, Oxyphenbutazone, Piroxicam, Prednisolone,Prednisone, Suprofen and Triamcinolone (and Acetonide).

16. Anti-Malarial agents such as Pyrimethamine.

17. Anti-Parkinson's and/or Anti-Alzhiemer's agents such as Biperiden,Bromocriptine, Cabergoline, 1-Hydroxy-Tacrine, Levodopa, Lisuride,Pergolide, Pramipexole, Quinpirole, Ropinirole, Rivastigmine,Physostigimine, Selegiline (Deprenyl and L-Deprenyl), Tacrine andTeruride.

18. Anti-Psychotic and/or Anti-Anxiety and/or Anti-Depressant agentssuch as Acetophenazine, Bromperidol, Chlorproethazine, Chlorpromazine,Clomipramine, Clozapine, Fluoxetine, Fluphenazine, Haloperidol,Loxapine, Mesoridazine, Molindone, Paroxetine, Perphenazine,Piperacetazine, Sertraline, Thiopropazate, Thioridazine, Thiothixene,Trifluoperazine, Triflupromazine and Venlafaxine.

19. Anti-Ulcerative agents such as Enprostil and Misoprostol.

20. Anti-Viral agents such as Acyclovir, Rimantadine and Vidarabine.

21. Anxiolytic agents such as Azapirones such as Buspirone andIpsapirone, Benzodiazepines such as Alprazolam, Chlordiazepoxide,Clonazepam, Clorazepate, Diazepam, Flurazepam, Halazepam, Lorazepam,Oxazepam, Oxazolam, Prazepam and Triazolam.

22. B-Adrenergic agonist agents such as Albuterol, Carbuterol,Fenoterol, Metaproterenol, Mirtazapine, Rimiterol, Quinterenol,Salmefamol, Soterenol, Tratoquinol, Terbutaline and Terbuterol.

23. Bronchodilators such as Ephedrine derivatives, Epiniphrine,Isoproterenol, Albuterol, Salbutanol, Clenbuterol and Theophylline.

24. Cardioactive agents such as Atenolol, Benzydroflumethiazide,Bendroflumethiazide, Calcitonin, Captopril, Chlorothiazide, Clonidine,Clopamide, Dobutamine, Dopamine, Diltiazem, Enalapril, Enalaprilat,Gallopamil, Indomethacin, Isosorbide (Dinitrate and Mononitrate),Monoxidil, Nicardipine, Nifedipine, Nitroglycerin, Papaverine, Prazosin,Procainamide, Propranolol, Prostaglandin (E.sub.1 and E.sub.2),Quinidine Sulfate, Timolol, and Verapamil.

25. Central Nervous System stimulants and agents such asDextroamphetamine, Methylphenidate (and each Enantiomer and Free BaseForm) and Nicotine.

26. Cholinergic agents such as Acetylcholine, Arecoline, Bethanechol,Carbachol, Choline, Methacoline, Muscarine and Pilocarpine.

27. Muscle relaxants such as Baclofen.

28. Narcotic antagonist agents such Nalmfene and Naloxone.

An oral enteric controlled release drug delivery system of matrixmicrospheres with near zero order kinetics was developed in accordancewith the instant invention. The experimental details of the preparationand analyses of these microspheres are presented hereinafter inExample 1. Polymer mixtures of a pH sensitive polymer, cellulose acetatephthalate (CAP) and a pH insensitive polymer, cellulose acetate butyrate(CAB381-20) of various ratios were used to obtain the desired constantrelease rate of theophylline from matrix microspheres. Microspheres with33% theoretical drug loading of anhydrous micronized theophylline corematerial were prepared by the emulsion solvent evaporation method.Dissolution studies were conducted with USP dissolution Apparatus II at37° C. using simulated gastric fluid without enzymes for the first twohours followed by simulated intestinal fluid (SIF) without enzymes for24 hours. The release mechanism of microspheres in SIF may be similar toa porous reservoir system where the drug is concentrated in the centralpart of the microspheres. The release kinetics of theophylline from180-500 μm size range microspheres containing the polymer mixturefollowed near zero order release kinetics for all formulations that werestudied. The microsphere preparations are therefore useful for oraldelivery of theophylline and other drugs.

In the embodiment described, CAP polymer is used with CAB381-20 inmatrix microspheres prepared by emulsion-solvent evaporation in order to(a) increase theophylline release rates (b) achieve a pH dependentrelease dosage form, i.e. enteric matrix dosage form, and (c) controlthe drug release rates so that zero order release kinetics are achievedin matrix microspheres.

Microsphere Preparation

Table 1 shows the different formulas prepared from the polymer mixtureCAP and CAB381-20 using an emulsion solvent evaporation method inaccordance with the instant invention. The most successful microspherepreparations were those using CAB 381-20 at concentrations 7.5 to 8.5%(w/w) of the total polymer concentration dissolved in acetone and CAP ata ratio of 1-2.5% to that of the total polymer concentration.

Particle Size Distribution

One of the methods used to control the particle size distribution ofmicrospheres prepared by the solvent evaporation method is by alteringthe agitation intensity during emulsification process. In the presentinvention, particle size distribution of microspheres prepared with alldifferent polymer mixture solutions can be adjusted by altering theagitation intensity so that each yielded a similar particle sizedistribution. A typical log-probability plot of size distribution of M9microspheres with CAP percentage of 1% in a total polymer concentrationof 8% is shown in FIG. 1, where the size distribution of microspheres isgenerally narrow with geometric mean of about 240 μm and a geometricstandard deviation of 1.54 calculated from 50% undersize/16% undersize.

Drug Loading

The analysis of drug content of microspheres with a theoretical drugloading of 33.3% calculated from the weight of drug and polymer (theratio of weights of theophylline: CAB381-20 and CAP was 1:2) varied from24.0% -24.8% for 180-600 μm size fractions of microspheres. Nosignificant differences in drug loading were found between differentmicrosphere preparations.

Release Studies

Drug release from microspheres composed of a mixture of CAB381-20 andCAP polymers was determined to be related mainly to the dissolution rateof CAP and the integrity of the hydrophobic barrier of CAB381-20. CAPpolymer dissolves in the vicinity of pH 6 (24). Its dissolution ratedepends on the pH of the microenvironment of the dissolving polymer. Ithas been reported that the dissociation of CAP polymer in thedissolution fluid is the rate-determining step in its dissolution. TABLE1 Microsphere formulas prepared from the polymer mixture CAP andCAB381-20 polymer mixture using the emulsion-solvent evaporation method.All formulas contained micronized anhydrous theophylline to give atheoretical concentration of 33.3% in the microspheres. Total polymerConcentration of CAP as concentration in the polymer Formula apercentage of the total polymer solution phase (% W/W) M1 25 10 M2 10 10M5 1 7.5 M6 2 7.5 M7 5 7.5 M8 1 8 M9 2.5 8  M10 1 8.5 M3 2.5 8.5  M11 58.5

The rate of proton transfer is governed by the Bronsted Catalyst Law andthe greater the pKa and the concentration of the basic salt used in thebuffered dissolution medium, the greater the dissolution rate of CAP.Permeability of a material to water and drugs plays an important role indetermining the overall dissolution of CAP microspheres. Entericmaterials should be impermeable to the gastric fluid, which has a lowpH.

Drug dissolution profiles are shown in FIGS. 2-7 for different sizefractions of microspheres of various microsphere preparations. Thesedissolution profiles can be divided into three stages.

Initial release stage: a small initial drug release was noticed just fewminutes after suspending the microspheres in the acid dissolutionmedium; and higher release rates were associated with smaller sizefractions. This may be because, during the initial stage, the drug at ornear surface of the microspheres quickly diffused through thebuffer-filled pores of the polymer mixture. For the same weight sample,smaller particles have greater surface and therefore have more drug nearthe surface for the initial rapid release phase.

Release in acid after initial stage: Most of the drug released in theinitial stage is due mainly to drug at or near the surface and could beremoved with an acid wash prior to the dissolution analysis. After theinitial release and during the dissolution in the acidic environment(SGF, pH 1.2, 37° C.) the profile of most formulations flattens outuntil the media pH is increased. However, a slight increase in theamount of drug released at the end of the acid stage. This behavior ofmatrix microspheres containing CAP in the acidic media could beexplained by the hygroscopic properties of CAP. Higher permeabilitycould be due also to the preparation method. It has been reported thatthe use of highly volatile solvents in sprayed films yield films with avery high degree of porosity. The use of highly volatile solvents (suchas acetone) in microsphere preparation could increase the degree of theporosity of these microspheres containing low viscosity CAP. Also, CAPpolymer films, while continuous, can be permeable to ionic solutions andact as a diffusion membrane. Although drug was shown to leach out ofmicrospheres in the acidic region, the rates after the initial releasewere very low throughout the 2 hour period. This indicates that CAP doesnot dissolve in the acidic medium, but rather it has some permeability,taking into account that theophylline solubility in both acidic andalkaline media is quite similar due to its neutrality.

Slightly alkaline stage: During the dissolution in the slightlyalkaline-buffered medium (SIF, pH 7.5, 37° C.), higher release rateswere noticed for all microsphere size fractions. Slopes of the releaseprofiles in the acidic and the slightly alkaline dissolution media arecompared in Tables 2 and 3 where correlation coefficients are alsoshown. It is evident that slopes are larger in the slightly alkalinemedia indicating higher theophylline release rates in this medium.Moreover, the release rates are independent of time (zero orderkinetics) for all microsphere formulations and size fractions that werestudied. Different rates of drug release are observed when comparingformulations containing different ratios of CAP and CAB381-20 as shownin FIGS. 8, 9 and 10. The dissolution profiles at this stage indicatethat the CAP polymer at the surfaces and within the outer polymer matrixdissolves quickly leaving behind a porous CAB381-20 membrane. At thistime the rate of liquid penetration is controlled by the porosity of themicrosphere. As dissolution times increase, more CAP dissolves creatinga porous environment for more water to penetrate the microsphereaccompanied with more drug diffusion and release. These pores arebelieved to be small in size and are proportional to the ratio of CAP inthe formula, but they are believed to be uniformly distributedthroughout the matrix. At the low CAP polymer ratios in the microspherepreparations, release rates are regulated mainly through the porousenvironment created from CAP leaching out. The porosity created in thepolymers allows water to penetrate and drug molecules to leach out.

Microscopy studies indicate that the drug is concentrated toward thecentral portion of the microspheres thus forming a reservoir of drug forcontrolled diffusion.

Release kinetics: The release of a drug is usually a diffusion processthat depends on the environment of the drug unit. T. Higuchi publishedequations to describe the release of drug from planar and sphericalmatrix systems. For most matrix microspheres, the rate of drug releasefrom a granular spherical pellet usually can be described by the Higuchimatrix model, which can be written as shown in the following equation:1+2F−3F ^(2/3) =Kt

Where F is the fraction of drug remaining at time t, K is a combinedconstant and K=6DC_(s)V_(sp)/τr₂ for the granular pellet, D is thediffusion coefficient, C_(s) is the solubility of the drug in the matrixor the dissolution fluid in the matrix pores, V_(sp) is the specificvolume of the drug, τ is the tortuosity of the porous system and r isthe radius of the microspheres. In this study release profiles did notfollow Higuchi spherical matrix release as shown in FIG. 11, instead anear zero order release pattern is seen in most CAB381-20, CAP mixturemicrospheres until about 80% of drug released. Then, the release ratesdecreased and reached plateau at about 90% of drug released. The degreeof this effect depends to large extent on the ratio of CAP in themicrosphere formulation as well as the total polymer concentration orviscosity in the organic phase. The preparations containing CAP could beadjusted to increase release rates as well as to obtain time independentrelease pattern. Furthermore, dissolution was also conducted for somepreparations in a buffer solution of pH 7.5 alone without using the acidmedia as a first stage. FIG. 12 show the release profile of M3preparations in phosphate buffer of pH 7.5. It was evident that T50% waslow compared to the same preparation tested in the two-stage dissolution(FIG. 2) due to the absence of the acid phase, which is considered as alag phase. It was also evident that the release profiles do follow nearzero order kinetics throughout most of the release times. TABLE 2 Slopesand correlation coefficients of release profiles of various microspherepreparations in pH 1.2 medium. 0-2 hours (in SGF) Correlationcoefficient for zero Formula Size Slope order mechanism M3 180-250 μm9.52 0.9994 355-500 μm 2.73 0.9534 M5 180-250 μm 5.86 0.9775 355-500 μm1.08 0.9026 M9 180-250 μm 6.94 0.9976 355-500 μm 2.35 0.9024  M10180-250 μm 5.84 0.9915 355-500 μm 2.63 0.9180

TABLE 3 Slopes and correlation coefficients of release profiles ofvarious microsphere preparations in the pH 7.5 medium Dissolution in SIFafter 2 hours in SGF Correlation coefficient for zero Formula Size Slopeorder mechanism M3 180-250 μm 13.26 0.9921 355-500 μm 3.91 0.9980 M5180-250 μm 11.15 0.9989 355-500 μm 3.32 0.9967 M9 180-250 μm 10.300.9962 355-500 μm 3.15 0.9980  M10 180-250 μm 9.75 1.0000 355-500 μm3.02 0.9971

In another embodiment of the instant invention, a water-swellingpolymer, hydroxypropylcellulose (HPC), was used in a polymer solutionphase containing a hydrophobic polymer, cellulose acetate butyrate (CAB381-20), to make matrix microspheres containing theophylline. Theexperimental details of the preparation and analyses of thesemicrospheres are presented hereinafter in Example 2. Release rates andrelease patterns of CAB381-20 were modified because of the swellingproperty of HPC in aqueous solutions. Optimization of these microsphereformulations provided a system that had near zero order releasekinetics.

Matrix microspheres were prepared by the emulsion solvent evaporationmethod using Span 83 as an emulsifier. Theophylline (theoreticalconcentration of 33.3%) was dispersed in different viscosities ofpolymer mixture solutions of CAB381-20 and HPC in acetone to yieldsimilar drug to polymer ratios. The concentration of HPC to CAB381-20 inthese formulas varied from 0.5-5% (w/w) with a total polymerconcentration of 7-9% (w/w) in acetone. Dissolution studies wereconducted with USP dissolution Apparatus II at 37° C. using simulatedintestinal fluid without enzymes as a dissolution medium. More thantwelve different formulas were prepared; some showed release patternsuseful for controlled release oral dosing. Rapid initial release wasnoticed with the incorporation of HPC and release rates increased in allformulas as the percentage of HPC increased. This is likely attributedto the property of HPC to swell in contact with water.

Most preparations followed the Higuchi spherical matrix model in theirdissolution. However, a few microsphere formulations made of HPC,CAB381-20 polymer mixture showed the ability to release the drug by nearzero order kinetics after an initial rapid release. At late stages(after 70-80% release) the kinetics tended to follow the Higuchispherical matrix model. Incorporating HPC to some extent in a polymerphase containing hydrophobic polymer CAB381-20 in microspherepreparation has a pronounced effect on the release of theophylline fromsuch microspheres. This effect is primarily related to thewater-swelling behavior of HPC. Table 4 shows the relative viscositiesof different formulations of various proportions of HPC and CAB381-20.It is clear that CAB381-20 is the main ingredient that determines theviscosity of the mixture due to its higher proportions in the formula,while HPC has mild effect at the concentrations employed.

Size Distribution

One of the methods used to control the particle size distribution ofmicrospheres prepared by solvent evaporation method is by altering theagitation intensity during emulsification process. It was evident that achange in polymer viscosity has a substantial influence on particle sizedistribution, with higher viscosities favoring larger particle size. InCAB-HPC embodiments, particle size distribution of microspheres preparedwith all different polymer mixture solutions could be adjusted byaltering the agitation intensity to yield similar particle sizedistribution. A typical log-probability plot of size distribution of K7microspheres preparation with a ratio HPC:CAB381-20 of 2% is shown inFIG. 13, where the size distribution of microspheres is generally narrowwith geometric mean of about 280 μm and a geometric standard deviationof 1.7 calculated from 50% undersize/16% undersize.

Drug Loading

The analysis of drug content of microspheres with a theoretical drugloading of 33.3% calculated from the weight of drug and polymer (theratio of weights of theophylline: CAB381-20 and HPC was 1:2) varied from24.6-25.8 for 180-600 μm size fractions of microspheres. The averagedrug loading was higher when HPC was combined with CAB381-20 rather thanthat of CAB381-20 alone.

Release Studies

Previous studies on microspheres prepared using CAB381-20 at apparentviscosities of (115-240 cps) showed extended release profiles (T50% is40-60 hours for 180-250 μm microspheres) of the encapsulatedtheophylline. Matrix microspheres containing combined polymers ofdifferent characteristics (CAB381-20 and HPC) were prepared at differentratios, but constant drug to total polymer ratio (theoretical drugconcentration is 33.3%). Different formulas were prepared; some assummarized in Table 4.

Dissolution studies were conducted for microsphere size fractions of 180μm, 250 μm, 355 μm and 600 μm for at least 24 hours in simulatedintestinal fluid without enzymes. FIGS. 14-16 show the dissolutionprofiles of K3, K6 and K7 microspheres preparations respectively. It isshown that release rates increased with a decrease in microsphere sizes.Also it is evident from these figures that an increase in HPC ratio isaccompanied by a significant increase in theophylline release rates.This is seen more clearly when comparing preparations with fixed totalpolymer concentration but different HPC concentrations. Compared toCAB381-20 microspheres, T50% has been decreased with HPC being added.Total polymer solution viscosity also affects the magnitude of thisdecrease.

Unlike preparations K6, K3 and K5 which show release profiles near tothe zero order pattern after an initial rapid release, most preparationsshow matrix release which follows the Higuchi spherical matrix model asshown in FIGS. 17-19. These types of release could be explained asfollows: When a glassy (or dry) polymer, such as HPC, comes into contactwith water or any other medium which it is thermodynamically compatible,the solvent penetrates into the free spaces on the surface between themacromolecular chains. When enough water has entered into the matrix,the glass transition temperature (T_(g)) of the polymer drops to thelevel of the experimental temperature (which is usually 3720 C. forrelease studies) except for polymers that the T_(g) is far belowexperimental temperatures. Therefore polymers with a T_(g) greater than37° C. in their dry state can be used to prepare swelling controlledrelease dosage forms. TABLE 4 Formulas of HPC and CAB381-20 microsphereswith corresponding apparent viscosities. All formulas containedmicronized anhydrous theophylline to give a theoretical concentration of33.3% in the microspheres. Total polymer Concentration of concentrationin the HPC as polymer Apparent viscosity a percentage of the solutionphase of polymer solution Formula total polymer (W/W) phase (cps) K5 0.5%   7% 88 K13   1%   7% 81 K3    1% 7.5% 113 K12 1.5% 7.5% 109 K6   2% 7.5% 106 K7    5% 7.5% 98 K9  2.5%   8% 140 K15   5%   8% 130 K142.5% 8.5% 217 K16   5% 8.5% 203 K17 2.5%   9% 234 K18   5%   9% 228

HPC hydrates and swells in aqueous medium forming a gel; the presence ofHPC decreases the membrane barrier effect of the CAB381-20 by increasingthe water penetration into the microsphere and also by increasing theporosity of the microsphere structure. The degree of this effect dependsto large extent on the ratio of HPC in the microsphere formulation aswell as the total polymer concentration or viscosity in the organicphase. When the HPC to CAB381-20 ratio is in favor of increased porosityand water penetration, the drug leaches out in a way best described bythe Higuchi spherical matrix model (FIGS. 16, 18, and 19). However, insome cases, HPC ratio could be adjusted to increase release rates aswell as to obtain time independent release pattern. This could be seenin FIG. 14 (1% HPC in 7.5% total polymer concentration) and FIG. 15 (2%HPC in 7.5% total polymer concentration) where a near zero order releasepattern was obtained up to 70-80% for 30 and 10 hours respectively afteran initial rapid release.

These release patterns could be explained based on the swelling andrelaxation properties of HPC as mentioned earlier in addition to themodification of CAB381-20 microsphere structure as follows: In theinitial stage, the liquid (dissolution medium) rapidly dissolves thedrug present at the immediate surface of the microspheres. Asdissolution times increase, the swollen HPC allows more water topenetrate the microsphere and that is accompanied by countercurrent drugdiffusion. Thus in formulas K3 and K6 (FIGS. 14 and 15 respectively)water penetration and hence drug release are regulated by the swollenHPC and the barrier effect of CAB381-20. Therefore, it seems that HPChas disrupted the polymer barrier system exhibited by CAB381-20microspheres and transformed the system into a pseudo-reservoirstructure. This release pattern has been noticed in a few formulationshaving certain HPC to CAB381-20 ratios with a definite viscosity andthis can occur only at very limited combinations of those polymers wherethere is a balance the effects of both polymers ratios and the totalpolymer viscosity.

A comparison of the release rates of different microsphere formulationis shown in FIGS. 20 and 21, where release profiles from 180-250 μm and250-355 μm size fractions microspheres are shown, respectively. It wasevident that the viscosity of the initial polymer mixture solutions hasa significant effect on release rates and this effect is most obviouswhen the amount of HPC is kept constant. Viscosity of the polymersolution phase is mainly due to the CAB381-20 polymer that has a higherviscosity as well as higher proportion in the total polymer solutionphase. Lower apparent viscosities resulted in faster release rates andwith the addition of HPC to the microspheres matrix, release ratesincrease further. At higher total polymer viscosity, release ratesdecrease and higher proportions of HPC are required to compensate forthe increased viscosity. However, higher viscosities might show higherrelease rates when the proportion of HPC is increased so much. Forexample as shown in FIGS. 20 and 21, although formula K7 has higherinitial polymer solution viscosity than that of K5, the release ratesare higher in the first. This supports the hypothesis that the balancebetween the viscosity and the HPC concentration no longer holds and thewater swelling properties of HPC create high porosity and easy pathwaysfor the drug to be leached out.

The release profile of theophylline in simulated gastric fluid; SGF (pH1.2) was also conducted for some preparations. It was anticipated thatrelease profiles would be very much similar due to the properties oftheophylline, which is neutral. Generally, release profiles in SGF werefound to be similar to those in SIF.

The invention is described further in the following examples, which areillustrative and not limiting.

EXAMPLE 1 Preparation and Analysis of CAB-CAP Microspheres

CAB-CAP microspheres of the instant invention described herein wereprepared and analyzed as follows.

Experimental

Materials

The materials used were obtained from the following commercial suppliersand used without further purification. Cellulose acetate butyrate(CAB381-20, Eastman Chem. CO. lot. C-2769-B), cellulose acetatephthalate (CAP, Aldrich Chemical Company Lot 06715TG), theophylline(lot. No. 93237, Knoll AG), sorbitan sesquioleate (Arlacel 83, Sigma),acetone, hydrochloric acid, 36.5-38.0% (J. T. Baker Inc., Phillipsburg,N.J.), heptane (GFS Chemicals, Inc., Columbus, Ohio), mineral oil (RugerChemical Co. Inc., Irvington, N.J.). methylene chloride, sodiumphosphate tribasic and sodium chloride crystals (Fisher Scientific, NJ).

Instruments

Stirrer (Lab. Stirrer LR 4000, Yamato Scientific Co., LTD, Tokyo,Japan), USP Dissolution Apparatus II (Dissolution test system 5100,Distek, Inc., North Brunswick, N.J.), UV Spectrophotometer (Spectronic2000, Bausch & Lomb, Rochester, N.Y.), Accumet pH meter 5 (FisherScientific, NJ), standard sieve series.

Preparation of Microspheres

Microspheres containing micronized anhydrous theophylline of atheoretical concentration of 33.3% were prepared by the non-aqueousemulsion-solvent evaporation method using cellulose acetate butyrate(CAB 381-20, M. W. of 70,000) at concentrations 7.5 to 10% (w/w) of thetotal polymer concentration dissolved in acetone and cellulose acetatephthalate (CAP, M. W. 42,000) at ratios of 1-5% of the total polymerconcentration. Theophylline powder was dispersed in the above mentionedpolymer solution mixtures to yield the required drug to polymer ratios.Sorbitan sesquioleate was used as an emulsifying agent. The stirrerconsisted of two propellers on a single shaft. Each propeller containedthree blades with a diameter of 25 mm. The dispersion system wascontinuously stirred at a constant adjusted speed (750-1500 rpm)depending on the viscosity of polymer solutions. After the formation ofmicrospheres and the evaporation of solvent, the microspheres wereseparated from the oil phase, washed with n-heptane and dried at 50° C.At least two identical batches were prepared of each formula.

Particle Size Distribution

Size distributions were evaluated by sieve analysis using a set ofstandard sieves with openings from 106 to 600 μm. The microspheres wereplaced at the topmost sieve and tapped by hand. The weight ofmicrospheres retained on each individual sieve was recorded and themicrospheres were stored for further characterization.

Drug Loading

Drug content analysis was performed by accurately weighing about 5 mgsamples of microspheres in a 10-ml volumetric flask. A mixture ofmethylene chloride and ethanol at a ratio of 3:1 was added to dissolvethe polymer and the drug. Drug concentration was determinedspecrophotometric analysis at 274-nm wavelength. Although there weresmall amounts of phthalate containing polymer in the microspheres, therewas insignificant interference with the drug analysis.

Dissolution Analysis

In vitro dissolution studies were carried out on the microspheres at 37°C. (±0.5° C.) at 100 rpm with USP dissolution apparatus II using theprocedure for enteric-coated products. For the acid stage, an accuratelyweighed sample of microspheres (25-30 mg) was suspended in thedissolution media consisting of 525 ml of 0.1 N hydrochloric acidwithout enzymes and dissolution was done for 2 hours. At the end of the2 hours, 375 ml of 0.1 M tribasic sodium phosphate was added to alldissolution vessels, the pH was adjusted to 7.5 and the dissolution wascontinued for 24 hours for the buffer stage. Aliquots of dissolutionfluid were withdrawn at specified time intervals to assay the releaseddrug spectrophotometrically at 271 nm. Dissolution was carried out forat least 24 hours. Each graphical data point was an average ofdissolution data from three samples. Corrections were made for theremoval of samples. The interference of polymers with the absorbance isnegligible (maximum of 0.002 absorbance units) due to the small amountof phthalate in CAP polymer (phthalic acid absorbance maximum is at 281nm in phosphate buffer).

EXAMPLE 2 Preparation and Analysis of CAB-HPC Microspheres

CAB-HPC microspheres of the instant invention described herein wereprepared and analyzed as follows.

Experimental

Materials

Cellulose acetate butyrate (CAB381-20, Eastman Chem. CO. lot. C-2769-B),hydroxypropyl cellulose (HPC, Scientific Polymer Products Inc., CAT#402, Lot 1), theophylline (lot. No. 93237, Knoll AG), sorbitansesquioleate (Arlacel 83, Sigma), acetone (J. T. Baker Inc.,Phillipsburg, N.J.), heptane (GFS Chemicals, Inc., Columbus, Ohio),methylene chloride (Fisher Scientific, NJ), mineral oil (Ruger ChemicalCo. Inc., Irvington, N.J.). Potassium phosphate monobasic and sodiumhydroxide 50% w/w solution (J. T. Baker Inc., Phillipsburg, N.J.).

Instruments

Stirrer (Lab. Stirrer, LR 4000, Yamato Scientific Co., LTD, Tokyo,Japan), USP dissolution apparatus II (dissolution test system 5100,Distek, Inc., North Brunswick, N.J.), UV spectrophotometer (Spectronic2000, Bausch & Lomb, Rochester, N.Y.), Accumet pH meter 5 (FisherScientific, NJ), standard sieves series, viscometer DV-II (BrookfieldEngineering Laboratories, Inc. Stoughton, Mass.)

Preparation of Microspheres

Microspheres containing micronized anhydrous theophylline in atheoretical concentration of 33.3% were prepared by the emulsion-solventevaporation method using the polymers (CAB 381-20, MWT of 70,000) atconcentrations 7 to 9% (w/w) of the total polymer concentrationdissolved in acetone and (HPC, MWT 100,000) at a ratio of 0.5-5.25% tothat of CAB381-20. Theophylline powder was dispersed in theabove-mentioned polymer solution mixtures to yield the required drug topolymer ratios. Arlacel 83 was used as an emulsifying agent. The stirrerconsisted of two propellers on a single shaft. Each propeller had adiameter of 25 mm and contained three blades. The dispersion system wascontinuously stirred at a constant adjusted speed (750-1250 rpm)depending on the relative viscosity of polymer solutions. After theformation of microspheres and the evaporation of solvent, themicrospheres were separated from the oil phase, washed with n-heptaneand dried at 50° C. At least two identical batches were prepared of eachformula.

Viscosity of the Polymer Phase

Viscosities of the polymer mixture solutions were determined with aBrookfield digital viscometer using the small sample adapter withspindles No. 18 and No. 21, as appropriate, at 20 rpm.

Particle Size Distribution

The size distributions were evaluated by sieve analysis using a set ofstandard sieves from 106 to 600 μm. The microspheres were placed at thetopmost sieve and tapped by hand. The weight of microspheres retained oneach individual sieve was recorded.

Drug Loading

A 5-mg sample of microspheres was placed in a 10-ml volumetric flask andmethylene chloride was added to dissolve the polymers and the drug. Drugconcentration was determined specrophotometrically at 274-nm wavelength.At the specified wavelength, no spectrophotometric interferences wereobserved from an equivalent quantity of the blank microspheres(microspheres without theophylline).

In Vitro Drug Dissolution Analysis

In vitro dissolution studies were carried out on the microspheres at 37°C. (±0.5° C.) in 900 ml of simulated intestinal fluid (SIF) USP withoutenzyme at 100 rpm using USP dissolution apparatus II. Accurately weighedsamples of microspheres (25-30 mg) were suspended in the dissolutionmedia and an aliquot of dissolution fluid was withdrawn at specifiedtime intervals to assay the released drug spectrophotometrically at 271nm. Dissolution was carried out for at least 24 hours. Each graphicaldata point was an average of dissolution data from three samples.Corrections were made for the removal of samples.

1. Microspheres comprising an active ingredient dispersed within apolymeric composition comprising a first pH insensitive hydrophobicpolymer and second pH sensitive hydrophobic polymer, wherein themicrospheres, in an aqueous environment having a pH of around 5 orgreater, release the active ingredient in a substantially zero-orderprofile, and wherein: (a) the microspheres are formed by a non-aqueousemulsion solvent evaporation method in which the first and secondpolymers and active ingredient are dispersed in an organic solvent toform a polymer solution phase, the polymer solution phase is emulsifiedinto a second continuous phase comprising a second solvent and asurfactant to form an emulsified dispersion system, and the emulsifieddispersion system is agitated and organic solvent evaporated therefromto form the microspheres; (b) the concentration of the second polymer asa percentage of total polymer in the polymer solution phase ranges fromaround 1% to 35% and total polymer concentration in the polymer solutionphase ranges from around 5% to around 35%; (c) microsphere particlediameter ranges from approximately 25 μm to approximately 1,000 μm; (d)the weight percentage of active ingredient in a microsphere ranges fromaround 5% to around 50%; and (e) active ingredient concentration ishighest in the microsphere core.
 2. Microspheres of claim 1, wherein:(a) the first and second polymers are selected from the group consistingof cross-linked polyvinyl alcohol, polyvinyl chlorides, regeneratedinsoluble non-erodible cellulose, acylated cellulose, esterifiedcelluloses, cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate phthalate, cellulose acetate diethyl-aminoacetate,polyurethanes, polycarbonates, and microporous polymers formed byco-precipitation of a polycation and a polyanion modified insolublecollagen; (b) the organic solvent is a halogenated hydrocarbon, analcohol, acetonitrile, or ketone, or mixture thereof; (c) the secondsolvent is silicone oil, sesame oil, soybean oil, corn oil, cottonseedoil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane, ormixtures thereof; and (d) the surfactant is an anionic surfactant,nonionic surfactant, polyoxyethylene-castor oil derivative,polyvinylpyrrolidone, polyvinyl alcohol, lecithin, or sorbitansesquioleate, or mixtures thereof.
 3. Microspheres of claim 1, whereinthe first and second polymers are selected from the group consisting ofcellulose acetate dimethylamino acetate, cellulose acetate ethyl andmethyl carbonate, cellulose acetate phthalate, cellulose acetatesuccinate, cellulose acetate chloroacetate, cellulose diacetate,cellulose triacetate, cellulose acetate ethyl oxalate, cellulose acetatetrimellitate, hydroxypropyl methylcellulose phthalate, cellulose acetatemethyl and butyl sulfonate, cellulose acetate octate, cellulose acetatelaurate, cellulose acetate p-toluene sulfonate, cellulose acetate ethylcarbamate, cellulose acetate methyl carbamate, cellulose acetatevalerate, cellulose acetate maleate, and combinations and mixturesthereof.
 4. Microspheres of claim 1, wherein the first and secondpolymers are selected from the group consisting of cellulose acetate,cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, cellulose acetate trimellitate, cellulose propionatebutyrate, and combinations and mixtures thereof.
 5. Microspheres ofclaim 1, wherein the first polymer is cellulose acetate butyrate (CAB)and the second polymer is cellulose acetate phthalate (CAP). 6.Microspheres of claim 5, wherein the total concentration of polymer inthe polymer solution phase is between around 5% to around 15%. 7.Microspheres of claim 6, wherein the total concentration of CAP in thepolymer solution phase as a percentage of total polymer is betweenaround 1% to 30%.
 8. Microspheres of claim 7, wherein the averagemicrosphere size is 100 μm to 700 μm.
 9. Microspheres of claim 8,wherein the total concentration of CAB in the polymer solution phase isbetween around 7% to around 9%, the total concentration of CAP in thepolymer solution phase as a percentage of total polymer is betweenaround 1% to 3%, and the microspheres are 150 μm to approximately 350 μmin size.
 10. Microspheres of claim 8, wherein the microspheres comprisearound 30% to around 35% by weight of one or more of the followingactive ingredients: an alpha-adrenergic agonist an analgesic oranti-migraine agent, an anti-allergic agent, an anesthetic agent, ananoretic agent, a anti-bacterial (antibiotic) agent an anti-canceragent, an anti-cholinergic agents an anti-diabetic agent, an anti-emeticagent, an anti-fungal agent an antihistamine agent, ananti-hyperlipoproteinemic agent, an anti-hyperthyroid agent, ananti-inflammatory or corticoid agent, an anti-malarial agent, ananti-Parkinson's or Anti-Alzheimer's agent, an anti-psychotic,anti-anxiety or anti-depressant agent, an anti-ulcerative agent, ananti-viral agent, an anxiolytic agent, a B-Adrenergic agonist agent, abronchodilator, a cardioactive agent, a central nervous systemstimulant, a cholinergic agent, a muscle relaxant, and a narcoticantagonist agent.
 11. Microspheres of claim 5, wherein the organicsolvent is acetone, the surfactant is sorbitan sesquioleate, and theactive ingredient is theophylline.
 12. Microspheres of claim 5, wherein,upon dispersion of the microspheres into an aqueous environment having apH of around 5 or greater, substantially all of the active ingredient isreleased from the microspheres in between around 12 to 24 hours. 13.Microspheres of claim 12, wherein substantially all of the secondpolymer dissolves in the aqueous environment upon release ofsubstantially all of the active ingredient from the microspheres.
 14. Acontrolled-release pharmaceutical composition comprising microspheres ofclaim
 1. 15. A controlled-release pharmaceutical composition of claim14, wherein the pharmaceutical composition is a tablet.
 16. Acontrolled-release pharmaceutical composition of claim 14, wherein thepharmaceutical composition is administered orally, parenterally, byinhalation spray, topically, rectally, nasally, buccally, vaginally orvia an implanted reservoir
 17. A controlled-release pharmaceuticalcomposition of claim 14, wherein the pharmaceutical composition is atablet or capsule which, upon administration to a mammal, releasessubstantially all of the active ingredient in the mammal's smallintestine.
 18. Microspheres comprising an active ingredient dispersedwithin a polymeric composition comprising a first pH insensitivehydrophobic polymer and second water-swellable polymer, wherein themicrospheres, in an aqueous environment, release the active ingredientin a substantially zero-order profile, and wherein: (a) the microspheresare formed by a non-aqueous emulsion solvent evaporation method in whichthe first and second polymers and active ingredient are dispersed in anorganic solvent to form a polymer solution phase, the polymer solutionphase is emulsified into a second continuous phase comprising a secondsolvent and a surfactant to form an emulsified dispersion system, andthe emulsified dispersion system is agitated and organic solventevaporated there from to form the microspheres; (b) the concentration ofthe second polymer as a percentage of total polymer in the polymersolution phase ranges from around 0.25% to 10%, total polymerconcentration in the polymer solution phase ranges from around 5% toaround 35%, and the viscosity of the polymer solution phase ranges fromaround 20 cps to around 1000 cps, preferably about 50 to about 300 cps;(c) microsphere particle diameter ranges from approximately 25 μm toapproximately 1,000 μm; (d) the weight percentage of active ingredientin a microsphere ranges from around 5% to around 50%; and (e) activeingredient concentration is highest in the microsphere core. 19.Microspheres of claim 18, wherein: (a) the first polymer is selectedfrom the group consisting of cross-linked polyvinyl alcohol,polyolefins, polyvinyl chlorides, cross-linked gelatins, regeneratedinsoluble non-erodible cellulose, acylated cellulose, esterifiedcelluloses, cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate diethyl-aminoacetate, polyurethanes, polycarbonates,and microporous polymers formed by co-precipitation of a polycation anda polyanion modified insoluble collagen; (b) the second polymer isselected from the group consisting of a low-substituted cellulose etheror internally cross-linked cellulose derivatives of sodiumcarboxymethylcellulose, hydroxypropyl-methylcellulose (HPMC), ahydroxypropylcellulose (HPC), a poly(ethylene oxide), anhydroxyethylcellulose, or a hydrogel forming polymer; (c) the organicsolvent is an alcohol, acetonitrile, ketone, or mixture thereof; (d) thesecond solvent is silicone oil, sesame oil, soybean oil, corn oil,cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane,n-heptane, or mixtures thereof; and (e) the surfactant is an anionicsurfactant, nonionic surfactant, polyoxyethylene-castor oil derivative,polyvinylpyrrolidone, polyvinyl alcohol, lecithin, or sorbitansesquioleate, or mixtures thereof.
 20. Microspheres of claim 19, whereinthe first polymer is selected from the group consisting of celluloseacetate dimethylamino acetate, cellulose acetate ethyl and methylcarbonate, cellulose acetate succinate, cellulose acetate chloroacetate,cellulose diacetate, cellulose triacetate, cellulose acetate ethyloxalate, cellulose acetate methyl and butyl sulfonate, cellulose acetateoctate, cellulose acetate laurate, cellulose acetate p-toluenesulfonate, cellulose acetate ethyl and methyl carbomate, celluloseacetate valerate, cellulose acetate maleate, and combinations andmixtures thereof.
 21. Microspheres of claim 20, wherein the firstpolymer is selected from the group consisting of cellulose acetate,cellulose acetate propionate, cellulose acetate butyrate, cellulosepropionate butyrate, and combinations and mixtures thereof. 22.Microspheres of claim 20, wherein the second polymer is a hydrogelformer.
 23. Microspheres of claim 18, wherein the first polymer iscellulose acetate butyrate (CAB) and the second polymer ishydroxypropylcellulose (HPC).
 24. Microspheres of claim 23, wherein thetotal concentration of polymer in the polymer solution phase is betweenaround 5% to around 15%.
 25. Microspheres of claim 24, wherein the totalconcentration of HPC in the polymer solution phase as a percentage oftotal polymer is between around 0.25% to 10%.
 26. Microspheres of claim25, wherein the average microsphere size is 100 μm to 400 μm. 27.Microspheres of claim 26, wherein the total concentration of CAB in thepolymer solution phase is between around 7% to around 9%, the totalconcentration of HPC in the polymer solution phase as a percentage oftotal polymer is between around 0.5% to 3%, and the microspheres are 150μm to approximately 350 μm in size.
 28. Microspheres of claim 27,wherein the microspheres comprise up to around 35% by weight of one ormore of the following active ingredients: an alpha-adrenergic agonist ananalgesic or anti-migraine agent, an anti-allergic agent, an anestheticagent, an anoretic agent, a anti-bacterial (antibiotic) agent ananti-cancer agent, an anti-cholinergic agents an anti-diabetic agent, ananti-emetic agent, an anti-fungal agent an antihistamine agent, ananti-hyperlipoproteinemic agent, an anti-hyperthyroid agent, ananti-inflammatory or corticoid agent, an anti-malarial agent, ananti-Parkinson's or Anti-Alzheimer's agent, an anti-psychotic,anti-anxiety or anti-depressant agent, an anti-ulcerative agent, ananti-viral agent, an anxiolytic agent, a B-Adrenergic agonist agent, abronchodilator, a cardioactive agent, a central nervous systemstimulant, a cholinergic agent, a muscle relaxant, and a narcoticantagonist agent.
 29. Microspheres of claim 27, wherein the organicsolvent is acetone, the surfactant is Arlacel 83, and the activeingredient is theophylline.
 30. Microspheres of claim 23, wherein, upondissolution in an aqueous environment having a pH of around 5 or 6 orgreater, substantially all of the active ingredient is released from themicrospheres in between around 12 to 24 hours.
 31. A controlled-releasepharmaceutical composition comprising microspheres of claim
 18. 32. Acontrolled-release pharmaceutical composition of claim 31, wherein thepharmaceutical composition is a tablet.
 33. A controlled-releasepharmaceutical composition of claim 31, wherein the pharmaceuticalcomposition is administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir.
 34. A controlled-release pharmaceutical composition of claim32, wherein the pharmaceutical composition is a tablet which, uponadministration to a mammal, releases substantially all of the activeingredient in the mammal's small intestine.
 35. A method of makingmicrospheres comprising: (a) dispersing a first pH insensitivehydrophobic polymer, a second pH-sensitive hydrophobic polymer, and anactive ingredient in an organic solvent to form a polymer solutionphase; (b) emulsifying the polymer solution phase into a secondcontinuous phase comprising a second solvent and a surfactant to form anemulsified dispersion system; and (c) agitating the emulsifieddispersion system and evaporating the organic solvent there from to formthe microspheres wherein (1) the concentration of the second polymer asa percentage of total polymer in the polymer solution phase ranges fromaround 0.25% to 10% and total polymer concentration in the polymersolution phase ranges from around 5% to around 35% (2) microsphereparticle diameter ranges from approximately 25 μm to approximately 1,000μm (3) the weight percentage of active ingredient in a microsphereranges from around 5% to around 40%, and (4) active ingredientconcentration is highest in the microsphere core.
 36. The method ofclaim 35, wherein: (a) the first and second polymers are selected fromthe group consisting of cross-linked polyvinyl alcohol, polyvinylchlorides, regenerated insoluble non-erodible cellulose, acylatedcellulose, esterified celluloses, cellulose acetate propionate,cellulose acetate butyrate, cellulose acetate phthalate, celluloseacetate diethyl-aminoacetate, polyurethanes, polycarbonates, andmicroporous polymers formed by co-precipitation of a polycation and apolyanion modified insoluble collagen; (b) the organic solvent is analcohol, acetonitrile, or ketone, or mixture thereof; (c) the secondsolvent is silicone oil, sesame oil, soybean oil, corn oil, cottonseedoil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane, ormixtures thereof; and (d) the surfactant is an anionic surfactant,nonionic surfactant, polyoxyethylene-castor oil derivative,polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose,lecithin, gelatin, hyaluronic acid, or sorbitan sesquioleate, ormixtures thereof.
 37. The method of claim 35, wherein the first andsecond polymers are selected from the group consisting of celluloseacetate dimethylamino acetate, cellulose acetate ethyl and methylcarbonate, cellulose acetate phthalate, cellulose acetate succinate,cellulose acetate chloroacetate, cellulose diacetate, cellulosetriacetate, cellulose acetate ethyl oxalate, cellulose acetate methyland butyl sulfonate, cellulose acetate octate, cellulose acetatelaurate, cellulose acetate p-toluene sulfonate, cellulose acetate ethyland methyl carbomate, cellulose acetate valerate, cellulose acetatemaleate, and combinations and mixtures thereof.
 38. The method of claim35, wherein the first and second polymers are selected from the groupconsisting of cellulose acetate, cellulose acetate propionate, celluloseacetate butyrate, cellulose acetate phthalate, cellulose propionatebutyrate, and combinations and mixtures thereof.
 39. The method of claim35, wherein the first polymer is cellulose acetate butyrate (CAB) andthe second polymer is cellulose acetate phthalate (CAP).
 40. The methodof claim 39, wherein the total concentration of polymer in the polymersolution phase is between around 5% to around 15%.
 41. The method ofclaim 40, wherein the total concentration of CAP in the polymer solutionphase as a percentage of total polymer is between around 1% to 3%. 42.The method of claim 41, wherein the average microsphere size is 100 μmto 700 μm.
 43. The method of claim 42, wherein the total concentrationof CAB in the polymer solution phase is between around 7% to around 9%,the total concentration of CAP in the polymer solution phase as apercentage of total polymer is between around 1% to 3%, and themicrospheres are 150 μm to approximately 350 μm in size.
 44. The methodof claim 43, wherein the microspheres comprise up to around 35% byweight of one or more of the following active ingredients: analpha-adrenergic agonist an analgesic or anti-migraine agent, ananti-allergic agent, an anesthetic agent, an anoretic agent, aanti-bacterial (antibiotic) agent an anti-cancer agent, ananti-cholinergic agents an anti-diabetic agent, an anti-emetic agent, ananti-fungal agent an antihistamine agent, an anti-hyperlipoproteinemicagent, an anti-hyperthyroid agent, an anti-inflammatory or corticoidagent, an anti-malarial agent, an anti-Parkinson's or Anti-Alzheimer'sagent, an anti-psychotic, anti-anxiety or anti-depressant agent, ananti-ulcerative agent, an anti-viral agent, an anxiolytic agent, aB-Adrenergic agonist agent, a bronchodilator, a cardioactive agent, acentral nervous system stimulant, a cholinergic agent, a musclerelaxant, and a narcotic antagonist agent.
 45. The method of claim 43,wherein the organic solvent is acetone, sorbitan sesquioleate is used toemulsify the dispersion system, and the active ingredient istheophylline.
 46. The method of claim 43, wherein the microspheres, upondissolution in an aqueous environment having a pH of around 5 or 6 orgreater, substantially all of the active ingredient is released from themicrospheres in between around 12 to 24 hours.
 47. The method of claim43, wherein substantially all of the second polymer dissolves in theaqueous environment to release of substantially all of the activeingredient from the microspheres.
 48. A method of making microspherescomprising: (a) dispersing a first pH insensitive hydrophobic polymer, asecond water-swellable polymer, and an active ingredient in an organicsolvent to form a polymer solution phase; (b) emulsifying the polymersolution phase into a second continuous phase comprising a secondsolvent and a surfactant to form an emulsified dispersion system; and(c) agitating the emulsified dispersion system and evaporating theorganic solvent there from to form the microspheres wherein (1) theconcentration of the second polymer as a percentage of total polymer inthe polymer solution phase ranges from around 0.25% to 10%, totalpolymer concentration in the polymer solution phase ranges from around5% to around 35%, and the viscosity of the polymer solution phase rangesfrom around 50 cps to around 1000 cps (2) microsphere particle diameterranges from approximately 25 μm to approximately 1,000 μm (3) the weightpercentage of active ingredient in a microsphere ranges from around 5%to around 50%; and (4) active ingredient concentration is highest in themicrosphere core.
 49. The method of claim 48, wherein: (a) the firstpolymer is selected from the group consisting of cross-linked polyvinylalcohol, polyolefins, polyvinyl chlorides, acylated cellulose,esterified celluloses, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate diethyl-aminoacetate, polyurethanes,polycarbonates, and microporous polymers formed by co-precipitation of apolycation and a polyanion modified insoluble collagen; (b) the secondpolymer is selected from the group consisting of a low-substitutedcellulose ether or internally cross-linked cellulose derivatives ofsodium carboxymethylcellulose, hydroxypropyl-methylcellulose (HPMC), ahydroxypropylcellulose (HPC), a poly(ethylene oxide), or a hydrogelforming polymer; (c) the organic solvent is an alcohol, acetonitrile, orketone, or mixture thereof; (d) the second solvent is silicone oil,sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseedoil, mineral oil, n-hexane, n-heptane, or mixtures thereof; and (e) thesurfactant is an anionic surfactant, nonionic surfactant,polyoxyethylene-castor oil derivative, polyvinylpyrrolidone, polyvinylalcohol, lecithin, or sorbitan sesquioleate, or mixtures thereof. 50.The method of claim 48, wherein the first polymer is selected from thegroup consisting of cellulose acetate dimethylamino acetate, celluloseacetate ethyl and methyl carbonate, cellulose acetate succinate,cellulose acetate chloroacetate, cellulose diacetate, cellulosetriacetate, cellulose acetate ethyl oxalate, cellulose acetate methyland butyl sulfonate, cellulose acetate octate, cellulose acetatelaurate, cellulose acetate p-toluene sulfonate, cellulose acetate ethyland methyl carbamate, cellulose acetate valerate, cellulose acetatemaleate, and combinations and mixtures thereof.
 51. The method of claim48, wherein the first polymer is selected from the group consisting ofcellulose acetate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose propionate butyrate,and combinations and mixtures thereof.
 52. The method of claim 48,wherein the second polymer is a hydrogel forming polymer.
 53. The methodof claim 48, wherein the first polymer is cellulose acetate butyrate(CAB) and the second polymer is hydroxypropylcellulose (HPC).
 54. Themethod of claim 53, wherein the total concentration of polymer in thepolymer solution phase is between around 5% to around 35%.
 55. Themethod of claim 54, wherein the total concentration of HPC in thepolymer solution phase as a percentage of total polymer is betweenaround 0.25% to 10%.
 56. The method of claim 55, wherein the averagemicrosphere size is 100 μm to 400 μm.
 57. The method of claim 55,wherein the total concentration of CAB in the polymer solution phase isbetween around 7% to around 9%, the total concentration of HPC in thepolymer solution phase as a percentage of total polymer is betweenaround 0.5% to 3%, and the microspheres are 150 μm to approximately 350μm in size.
 58. The method of claim 55, wherein the microspherescomprise up to around 35% by weight of one or more of the followingactive ingredients: an alpha-adrenergic agonist an analgesic oranti-migraine agent, an anti-allergic agent, an anesthetic agent, ananoretic agent, a anti-bacterial (antibiotic) agent an anti-canceragent, an anti-cholinergic agents an anti-diabetic agent, an anti-emeticagent, an anti-fungal agent an antihistamine agent, ananti-hyperlipoproteinemic agent, an anti-hyperthyroid agent, ananti-inflammatory or corticoid agent, an anti-malarial agent, ananti-Parkinson's or Anti-Alzheimer's agent, an anti-psychotic,anti-anxiety or anti-depressant agent, an anti-ulcerative agent, ananti-viral agent, an anxiolytic agent, a B-Adrenergic agonist agent, abronchodilator, a cardioactive agent, a central nervous systemstimulant, a cholinergic agent, a muscle relaxant, and a narcoticantagonist agent.
 59. The method of claim 55, wherein the organicsolvent is acetone, Arlacel 83 is used to emulsify the dispersionsystem, and the active ingredient is theophylline.
 60. The method ofclaim 55, wherein, upon dissolution in an aqueous environment having apH of around 5 or 6 or greater, substantially all of the activeingredient is released from the microspheres in between around 12 to 24hours.